September 2024

Using flow cytometry and the BrdU pulse-chase technique, Kutyavin et al. nicely demonstrate the existence of three eosinophil subpopulations in the SI: a young subset located around the crypts expressing α4β7; an intermediate subset lacking α4β7 and CD22 expression; and a mature subset, expressing CD22, found in the upper part of the villi. Through bulk RNA sequencing, they showed that this mature subset is best adapted to the SI microenvironment. Interestingly, this mature CD22+ subset, as well as the younger α4β7+ subset, appears to correspond to Clec4a4 positive and negative subsets previously identified in the work of Wang et al. (Wang WL, et al. Proc Natl Aca Sci U S A. 2022 Jun;119(23)). Additionally, Kutyavin et al highlight the role of amino acids and retinoic acid (RA) signaling in the accumulation and survival of SI-resident eosinophils. Using animal models, they demonstrated that disrupting the RA pathway by inhibiting its receptor, RAR, induces selective loss and increased turnover of the mature eosinophil subset. Furthermore, as RA is a nutrient-derived signal, the study showed that the composition of the diet, particularly the quantity of amino acids, has a significant impact on eosinophil adaptation to the SI environment. These findings echoes with the recent work by Diny et al. (Diny NL, et al. J Exp Med. 2022 Apr;219(4)), which also emphasized the crucial role of nutrients in the tissue adaptation of eosinophils in the SI.

Kutyavin et al.'s study significantly advances our understanding of eosinophil tissue adaptation in the SI. It provides valuable insights into the role of nutrient-derived signals, such as RA and amino acids, in regulating eosinophil populations. The study also raises interesting questions, such as the source of RA, the specific amino acids involved, and whether the enhanced survival of mature eosinophils is a direct effect of RA or mediated indirectly, possibly through the induction of markers associated with a longer lifespan. Given CD22’s previously described negative role of regulating small intestinal eosinophil levels (Wen et al, J. Immunol. 188, 1075–1082 (2012), there remains much to further uncover.

The study utilized single-cell RNA sequencing and single-cell proteomics combined with high-dimensional flow cytometry to capture the early stages of murine eosinophil development from bone marrow progenitors. It demonstrated that human eosinophilopoiesis closely resembles that of mice. Furthermore, the researchers showed that the expansion of eosinophil progenitors in models of eosinophilic conditions, such as asthma, eosinophilic esophagitis, and hypereosinophilic syndrome, is driven by increased transit amplification, a process where these progenitor cells rapidly multiply during their developmental phase before maturing into fully functional eosinophils, which relies on the slower acquisition of a fully mature phenotype and increased, prolonged proliferation capacity.

Using transgenic IL-5Rα reporter mice and conducting neutralization experiments, the authors demonstrated that IL-5 induces the stimulation and proliferation of eosinophilic progenitors but does not haved a role in the maturation process. This confirms previous observations that IL-5 deficient mice and asthmatics patients treated with anti-IL5 antibodies have a significant reduction in bone marrow and blood eosinophilia but the maturation of residual eosinophils remains uncompromised.This article is noteworthy due to its comprehensive approach, combining advanced single-cell technologies, including single-cell RNA sequencing and high-dimensional flow cytometry, allowing significant advancement in identifying the stages of eosinophil maturation. However, the study did not consider conditions of human eosinophilia nor examine precursors in all the biological environments, from the bone marrow to the blood.